It has been convincingly shown that nanotechnology can provide unique solutions to revolutionize diagnosis and treatment of many devastating diseases such as cancer. One specific area of great interest is development of nanoparticles for molecular specific imaging, therapy and combined imaging/therapy. A major roadblock in translation of inorganic nanoparticles to clinical practice for systemic targeting of cancer cells is their non-biodegradable nature. In addition, sizes of coated nanoparticles that are used in biological applications are not small enough to be easily cleared from the body. The accumulation and resulting long- term toxicity of nanoparticles is a major concern. In this research program we will create a new class of biodegradable gold nanoparticles with plasmon resonances in the NIR region. The nanoparticles will degrade to easily clearable components in the body and, therefore, will provide a crucial missing link between the enormous potential of metal nanoparticles for cancer imaging and therapy and translation into clinical practice. Our synthetic methodology is based on controlled assembly of very small (less than 5 nm) primary gold particles into nanoclusters with <100 nm overall diameter and an intense NIR absorbance. The assembly will be mediated by biodegradable polymers and small capping ligands on the primary nanoparticles. After delivery into the body the nanoclusters will biodegrade over time into sub-6 nm ligand capped primary gold nanoparticles, which will be highly favorable for rapid clearance from the body. This hybrid polymer/inorganic material will combine advantages of biodegradability of polymer nanoparticles and strong imaging contrast and therapeutic capabilities afforded by metal nanoparticles. Whereas these nanoclusters will be shown to have widespread potential in imaging/therapy, we will develop and optimize in this particular application biodegradable plasmonic nanoclusters with intense NIR absorbance for photo-acoustic imaging (PA) of cancerous cells. The nanoclusters will be evaluated in biologically relevant models of oral cancer. PUBLIC HEALTH RELEVANCE: It has been convincingly shown that nanotechnology can provide unique solutions to revolutionize diagnosis and treatment of many devastating diseases such as cancer. One specific area of great interest is development of nanoparticles for molecular specific imaging, therapy and combined imaging/therapy. A major roadblock in translation of inorganic nanoparticles to clinical practice for systemic targeting of cancer cells is their accumulation in the body and resulting long-term toxicity. In this research program we will create a new class of biodegradable gold nanoparticles with plasmon resonances in the NIR region. The nanoparticles will degrade to easily clearable components in the body and, therefore, will provide a crucial missing link between the enormous potential of metal nanoparticles for cancer imaging and therapy and translation into clinical practice.